Semaglutide and Cardiovascular Death: a Systematic Review and Meta-Analysis Cardioprotective Efficacy of Semaglutide

BACKGROUND: Cardiovascular death (CVD) remains a leading cause of global mortality. Although semaglutide reduces major adverse cardiovascular events (MACE), the consistency and exact magnitude of its standalone effect on CVD across various patient phenotypes require comprehensive evaluation. This meta-analysis systematically evaluated the clinical efficacy of semaglutide on CVD risk across randomized controlled trials (RCTs). METHODS: PubMed, Embase, and ClinicalTrials.gov were searched up to July 2026 to identify RCTs comparing semaglutide with placebo in adults with type 2 diabetes mellitus (T2DM), overweight or obesity, heart failure with preserved ejection fraction (HFpEF) or chronic kidney disease, reporting CVD as a primary, secondary or exploratory outcome. Pooled hazard ratio (HR) and 95% confidence intervals (CI) were calculated using a random-effects restricted maximum likelihood (REML) model. Publication bias and study robustness were assessed via Egger's test, Begg's test, and trim-and-fill analysis. RESULTS: Seven high-quality RCTs comprising 38412 patients were included. Semaglutide significantly reduced the risk of CVD by 17% compared with placebo (pooled HR = 0.83, 95% CI: 0.72-0.95; P = 0.01). Inter-study heterogeneity was low-to-moderate (I 2= 27.44%, P = 0.18). Subgroup analyses confirmed uniform benefits across different clinical phenotypes (T2DM; overweight or obesity without diabetes; and obesity-related HFpEF, with or without T2DM; P = 0.63) and administration routes (oral versus subcutaneous; P = 0.74). Meta-regression identified trial duration as a key moderator (R 2 = 85.27%, P = 0.089), whereas sex, age, BMI, HbA1c and concomitant SGLT2i therapy did not modify the treatment effect. Publication bias tests were non-significant, and trim-and-fill simulations confirmed the stability of the primary pooled estimate. CONCLUSION: Semaglutide delivers a robust and consistent 17% reduction in CVD across diverse cardiometabolic populations, including patients with T2DM, overweight or obesity without diabetes, and obesity-related HFpEF. These findings strongly support its role as a foundational cardioprotective intervention, independent of baseline glycemic status or the administration route.